People suffering from autoinflammatory disease (AID) have recurring sterile inflammation due to dysregulated inflammasome activation. Although certain genes have been associated with several AIDs, the molecular underpinnings of seemingly spontaneous inflammation are not well understood. Emerging data now suggest that mitochondrial reactive oxygen species (ROS), mitochondrial DNA (mtDNA), and autophagy might drive key signaling pathways towards activation of the inflammasome. In this review, we discuss recent findings and highlight common features between different AIDs and mitochondrial (dys)function. Although it is still early to identify clear therapeutic targets, the emerging paradigms in inflammation and mitochondrial biology show that mitochondria play an important role in AIDs, and understanding this interplay will be key in the development of new therapies.